Project summary/Abstract: Extensive evidence indicates that complement (C), in particular the C membrane attack complex (C/MAC), a key mediator of inflammation and immunity, plays a critical role in atherogenesis. However, mechanisms underlying C/MAC-accelerated atherogenesis is unknown. Recent trails of C-targeted therapeutics to inhibit C/MAC formation presented some benefit to reduce mortality in patients undergoing coronary artery bypass grafting but lack of consist benefit for myocardial infarction. Research to further understand mechanisms underlying C/MAC-accelerated atherogenesis is in great needs and would lead to the development of better therapeutic strategies for cardiovascular disease. We recently discovered that the deficiency of a key C/MAC regulator CD59 (mCd59-/-) induced monocytes (MC, CD11b+), inflammatory MC subset (CD11b+/Ly6C+) and caspase-1 (Casp1) activation in MC. We also demonstrated that Casp-1 activation plays an essential role in sensing metabolic danger signal-associated molecular patterns (DAMPs) and in initiating vascular inflammatory. These results link C/MAC formation with inflammatory MC differentiation, Casp1 activation and inflammasome activation in MC, which may contribute to vascular inflammation and atherogenesis. The effect of C/MAC on inflammatory MC differentiation and Casp-1 activation and its role in atherogenesis have not been studied before. In this project, we proposed four connected aims to investigate 1) the effect of C/MAC on MC expansion and differentiation, and atherosclerosis; 2) the molecular mechanism underlying C/MAC-induced Ly6C+ inflammatory MC differentiation; 3) the role of Casp-1 in C/MAC-induced Ly6C+ inflammatory MC differentiation and atherosclerosis; and 4) the therapeutic effect of C/MAC or Casp-1 inhibitors on C/MAC-induced MC differentiation and atherosclerosis. This study would provide important insights into our understanding about the role of complement system in atherosclerosis and inflammation, will open a new avenue to prevent and treat atherosclerosis, and will foster the development of new therapeutic strategies for cardiovascular disease.